CARRIER SYSTEMS
Liposomes are closed bilayer membranes containing an entrapped aqueous volume. Liposomes may be any variety of unilamellar vesicles (possessing a single membrane bilayer) or multilamellar vesicles (onion-like structures characterized by concentric lipid bilayers, each separated from the next by an aqueous layer).
Much has been written regarding the potential use of liposomes as drug delivery systems. In a liposomal drug delivery system, the medicament is entrapped during liposome formation and then administered to the patient to be treated. Typical of such disclosure are U.S. Pat. Nos. 3,993,754 issued on Nov. 23, 1976 to Rahman and Cerny, 4,145,410 issued on Mar. 20, 1979 to Sears, 4,235,871 issued Nov. 25, 1980 to Paphadjopoulos and Szoka, 4,224,179 issued Sept. 23, 1980 to Schneider, 4,356,167 issued Oct. 26, 1982 to L. Kelly, and 4,377,567 issued Sept. 13, 1979 to Geho.
Some of the problems encountered in using liposome preparations include instability of the liposomes during storage (e.g., liposomes cannot be stored as a dry powder); low entrapment of the incorporated drug; and the inability to completely decay in vivo so that a residual dose of the drug remains in the system (i.e., incomplete clearance of the drug).
A number of non-liposomal drug delivery systems have been described. In one, Schroder [Proceedings of the Controlled Release Society Meeting, San Francisco, July, 1983] used an aqueous carbohydrate solution in conjunction with an emulsifying system which, through sonication, effectively entrapped a number of proteins. When this preparation was added to acetone, spherical microcarriers of exceptional stability precipitated. Unfortunately, the stability of Schroder's microcarriers was such that the half-time for release of a number of proteins ranged from 5 to 15 days. When applied in vivo, such extreme carrier stability and resistance to biodegradation could lead to an immune reaction against the carrier, granuloma formation and/or capillary occlusion. (Targeting of Drugs, G. Gregoriadis, J. Senior and A. Trouet, eds., 268-272, Plenum Press, New York, 1982).
Chang (U.S. Pat. No. 4,317,743 issued Mar. 2, 1982) developed a microcapsule carrier composed of polyisocyanatoamide that entrapped hydrophobic substances, such as chemical dyes. These carriers displayed high heat stability and humidity resistance. At the same time, however, their formation required temperatures that would preclude their use as carriers of many pharmaceutical agents which are denatured at these temperatures. Moreover, their extreme stability necessitated the application of pressure, high temperature or other physical disruptive methods to cause the release of entrapped compounds.
Another type of delivery vehicle was developed by Sears (U.S. Pat. No. 4,298,594 issued Nov. 3, 1981). Using two synthetic approaches, Sears produced xenobiotic delivery vehicles composed of phospholipids and phospholipid-immiscible constituents, such as cholesterol esters or triglycerides. The result was microcarriers having diameters of 130-1000 angstroms and phospholipid compositions claimed to range from about 50 to 97 mole percent. However, these values appear to pertain to starting ratios, and no data are given as to how, or whether, the actual product composition was measured. These microcarriers were extremely stable at 37.degree. C. in buffered saline solution, showing no change in particle size after 30 days of incubation.